doi: /hepr.12514

Transcription

1 bs_bs_banner Hepatology Research 2016; 46: E5 E14 doi: /hepr Original Article Clinical characteristics and survival outcomes of super-elderly hepatocellular carcinoma patients not indicated for surgical resection Akiyoshi Kinoshita, 1 Hiroshi Onoda, 1 Kaoru Ueda, 1 Nami Imai, 1 Akira Iwaku, 1 Ken Tanaka, 1 Nao Fushiya, 1 Kazuhiko Koike, 1 Hirokazu Nishino 1 and Hisao Tajiri 2 1 Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital and 2 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Aim: Considering the dramatic increase in average life expectancy during the 20th century throughout the world, the management of elderly patients with cancer has become a global issue. We herein investigated the clinical characteristics and outcomes of super-elderly hepatocellular carcinoma (HCC) patients over 80 years old not indicated for surgical resection. Methods: We retrospectively evaluated 206 newly diagnosed HCC patients. The patients were divided into two groups according to their age at inclusion; a super-elderly group (n = 37, 80 years) and a younger group (n = 169, <80 years). We compared the clinical characteristics, overall survival (OS) and disease-specific survival (DSS) rates among the two groups. Both univariate and multivariate analyses were performed to identify the factors associated with the OS and DSS. Results: The proportion of women was higher in the superelderly group than in the younger group (P = 0.017). There were no significant differences in the OS (P = 0.171) or DSS (P = 0.176) between the two groups. The multivariate analysis revealed that only the Cancer Liver Italian Program score (hazard ratio [HR], 2.972; P < ; HR, 3.694; P < ) was independently associated with the OS and DSS. Age was not found to be associated with the OS or DSS according to either the univariate or multivariate analysis. Conclusion: There were no significant differences in the OS and DSS rates among the super-elderly HCC patients and younger HCC patients not indicated for surgical resection. An advanced age itself does not restrict the therapeutic approach, even in super-elderly HCC patients not indicated for surgical resection. Key words: clinical characteristics, elderly patients, hepatocellular carcinoma, prognosis INTRODUCTION HEPATOCELLULAR CARCINOMA (HCC) is a major health concern worldwide, and is the third cause of cancer-related death. 1,2 Approximately 90% of the cases of HCC are attributable to underlying liver diseases, such as chronic hepatitis B, chronic hepatitis C, alcohol abuse, non-alcoholic steatohepatitis (NASH) or aflatoxin exposure. 3 Despite advances in treatment, such as surgical resection, transplantation, percutaneous ablation and transarterial chemoembolization (TACE), and the administration of the multikinase inhibitor sorafenib, as Correspondence: Dr Akiyoshi Kinoshita, Division of Gastroenterology and Hepatology, Jikei University Daisan Hospital, Izumihon-cho, Komae-shi, Tokyo , Japan. aki.kino@jikei.ac.jp Conflictofinterest:The authors declare that they have no conflict of interest. Received 9 December 2014; revision 23 February 2015; accepted 26 February well as careful surveillance programs, the mortality rates in most countries are very similar to the incidence of HCC, thus reflecting the poor prognosis of this disease and the lack of effective treatments. 2 There has been a dramatic increase in the average life expectancy during the 20th century in many parts of the world. Thus, the management of elderly patients with cancer, including HCC, has become a global issue. In the USA, Canada and the UK, the highest agespecific rates occur among persons aged 75 years and older. 4 Japan has the highest life expectancy in the world, at 80.2 years for men and 86.6 for women. 5 Therefore, the opportunities to examine super-elderly HCC patients over 80 years old have significantly increased in Japan. Several investigators have reported the safety and favorable outcomes of surgical resection in super-elderly HCC patients over 80 years old E5

2 E6 A. Kinoshita et al. Hepatology Research 2016; 46: E5 E14 However, many patients with HCC present with intermediate to advanced stages of disease, and are not indicated for surgical resection at the initial diagnosis. Moreover, super-elderly patients have more comorbidities and more compromised liver regeneration than younger patients, indicating that they are poorer candidates for surgery. To the best of our knowledge, only a few studies have evaluated the clinical characteristics and outcomes of super-elderly HCC patients over 80 years old not indicated for surgical resection. Therefore, we herein investigated the clinical characteristics and outcomes of super-elderly HCC patients over 80 years old not indicated for surgical resection. METHODS Patients TWO HUNDRED AND forty-one patients with newly diagnosed HCC that had been treated in our department between January 2005 and December 2013 were enrolled in the study. All medical records were reviewed retrospectively. Sixteen patients had been lost to follow up. Nineteen patients who underwent surgical resection were also excluded. The remaining 206 patients were finally evaluated. The patients were divided into two groups according to their age at inclusion: a superelderly group (n = 37; 80 years) and a younger group (n = 169; <80 years). The diagnosis of HCC was confirmed either pathologically or by using imaging techniques including four-phase multidetector-row computed tomography (CT) or dynamic contrast-enhanced magnetic resonance imaging. The diagnosis was based on the typical hallmarks of HCC (hypervascular in the arterial phase with washout in the portal venous or delayed phases). 3 Tumor-related variables, such as the maximum tumor diameter, tumor number, presence of vascular invasion and presence of extrahepatic metastases, were evaluated. The Cancer Liver Italian Program (CLIP) score 14 and the Barcelona Clinic Liver Cancer (BCLC) classification 15 were calculated based on these imaging techniques and other variables. Data collection Blood samples were obtained before the initial treatment to measure the aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, creatinine (Cr) and albumin levels, as well as the platelet (Plt) count, prothrombin time (PT) and α-fetoprotein level (AFP). The Child Pugh grade 16 and the Model for End-Stage Liver Disease (MELD) score 17 were calculated based on these variables. Pretreatment comorbidities, such as hypertension, diabetes mellitus, other malignant disease, cardiovascular disease, cerebrovascular disease, pulmonary disease, renal failure and mental disease, were also evaluated. Treatment and patient follow up The decision to classify a patient as not suitable for surgical resection was made based on patient-related factors (medically unfit or unable to tolerate a major operation, or patient refusal of surgical resection) and tumor-related factors (extrahepatic metastasis or major invasion to the main portal vein or reduced liver functional reserve). Radiofrequency ablation (RFA) or a percutaneous ethanol injection (PEI) with/without TACE or transcatheter arterial infusion (TAI) chemotherapy was performed for patients with fewer than three lesions, where the lesions were each less than 3 cm in size. Patients with more than four lesions or those having lesions of 3 cm or more in size were treated by either TACE or TAI chemotherapy which included lipiodol, or by RFA/PEI with TACE/TAI chemotherapy. Either systemic chemotherapy or targeted therapy including sorafenib was administrated to patients with distant metastasis and preserved liver function. The best supportive care (BSC) was given to patients with a Child Pugh grade of C. In this study, curative treatment was defined as aggressive treatment that included either RFA/PEI or RFA/PEI with TACE/TAI chemotherapy within the Milan criteria ( 3 nodulesof 3cm). 18 In contrast, non-curative treatment was defined as any other palliative treatment (TACE, TAI, RFA/PEI with TACE/TAI chemotherapy beyond the Milan criteria (>3 nodules of >3cm),systemic chemotherapy, sorafenib or BSC). Patients were followed carefully after the initial treatment. The serum AFP levels were measured once every month. An ultrasound examination and a dynamic CT scan were performed every 3 months. Selective hepatic arterial angiography or a percutaneous biopsy was performed in patients with a suspected tumor recurrence. The start date of the follow up was the date of the initial diagnosis of HCC. The end date of the follow up was the time of the last follow up encompassed by this study (December 2013) or the time of the patient s death. This study complied with the standards of the Declaration of Helsinki and the current ethical guidelines, and was approved by the institutional ethics board. Written, informed consent for participation in this study was not obtained from the patients, because this study did not report on a clinical trial and the data were retrospective in nature and analyzed anonymously.

3 Hepatology Research 2016; 46: E5 E14 Super-elderly patients with HCC E7 Statistical analysis Comparisons between groups were performed using the Mann Whitney U-test for continuous and ordinal variables and the χ 2 -test test or Kruskal Wallis test for categorical variables. The overall survival (OS) rates were calculated using the Kaplan Meier method and differences in the survival rates between the groups were compared by the log rank test. To assess the potential prognostic factors, both univariate and multivariate analysis were performed using the Cox proportional hazard model. Variables that proved to be significant in the univariate analysis were tested subsequently with a multivariate Table 1 Clinicopathological characteristics of the patients Variable Super-elderly group (n = 37) Younger group (n =169) P n or median (range) n or median (range) Age (years) 82 (80 91) 71 (43 79) < Male sex (%) 55 (65%) 78 (76%) HBsAg positive (%) 1 (2.7%) 17 (10%) HCVAb positive (%) 25 (68%) 101 (60%) Non-HBV, non-hcv (%) 11 (30%) 51 (30%) Presence of cirrhosis (%) 20 (54%) 116 (69%) AST (IU/L) 46 (13 215) 58 (13 384) 0.01 ALT (IU/L) 30 (8 82) 46 (8 202) Total serum bilirubin (mg/dl) 0.5 ( ) 0.8 ( ) < Creatinine (mg/dl) 0.84 ( ) 0.74 ( ) Albumin (g/l) 3.6 ( ) 3.6 ( ) Platelet count ( 10 4 /mm 3 ) 15.3( ) 12.7 ( ) Prothrombin time (%) 82 (38 100) 79 (41 100) α-fetoprotein level (ng/ml) 17 ( ) 25 ( ) Child Pugh grade (A/B/C) 28/9/0 108/54/ MELD score 3 (1 19) 5 (1 25) CLIP score (0/1/2/3/4/5/6) 10/19/6/0/1/1/0 49/52/33/16/10/6/ BCLC stage (0/A/B/C/D) 6/17/12/2/0 24/81/29/28/ Maximum tumor diameter (mm) 30 (7 100) 29 (10 200) Multiple tumors (%) 16 (43%) 87 (51%) Vascular invasion present (%) 2 (5.4%) 21 (12%) Extrahepatic metastasis present (%) 0 (0%) 12 (7.1%) Curative treatment (%) 13 (35%) 75 (43%) Treatment modality RFA/PEI alone 6 (16%) 36 (21%) Combined TACE/TAI and RFA (within Milan/beyond Milan) 7/3 (27%) 43/20 (37%) TACE/TAI alone 20 (54%) 54 (32%) Sorafenib 1 (2.7%) 2 (1.2%) BSC 1 (2.7%) 14 (8.3%) Comorbidities present (%) (some overlap) 33 (89%) 122 (72%) 0.03 Hypertension 23 (62%) 76 (45%) Diabetes mellitus 12 (32%) 52 (31%) Other malignant disease 6 (16%) 26 (15%) Cardiovascular disease 8 (22%) 19 (11%) 0.09 Cerebrovascular disease 4 (11%) 6 (3.6%) 0.15 Pulmonary disease 1 (2.7%) 3 (1.8%) Renal failure 3 (8.1%) 8 (4.7%) Mental disease 1 (2.7%) 2 (1.2%) ALT, alanine aminotransferase, AST, aspartate aminotransferase, BCLC, Barcelona Clinic Liver Cancer classification, BSC, best supportive care, CLIP, the Cancer of the Liver Italian Program, HBsAg, hepatitis B surface antigen, HCVAb, hepatitis C antibody, MELD, Model for End-Stage Liver Disease, PEI, percutaneous ethanol injection, RFA, radiofrequency ablation, TACE, transarterial chemoembolization, TAI, transcatheter arterial infusion.

4 E8 A. Kinoshita et al. Hepatology Research 2016; 46: E5 E14 Cox proportional hazard model. P < 0.05 was considered statistically significant. All statistical analyses were performed using the IBM SPSS Statistics software program version 19.0 (IBM SPSS, Chicago, IL, USA). RESULTS Patient characteristics THE CLINICOPATHOLOGICAL CHARACTERISTICS of the patients are shown in Table 1. The proportion of women was higher in the super-elderly group than in the younger group (P = 0.017). The prevalence of patients with HBV infection or hepatitis C virus (HCV) infection showed no significant differences between the two groups. The presence of cirrhosis in the super-elderly group had a tendency to be lower than that in the younger group (P = 0.089). The serum AST (P = 0.01), ALT (P = 0.001) and total bilirubin levels (P < ) in the super-elderly group were lower than those in the younger group. There were no significant differences between the two groups with regard to the serum Cr level, the albumin, PT or AFP level, the Plt, Child Pugh grade, MELD score, CLIP score, BCLC classification, tumor diameter, tumor number, presence of vascular invasion, presence of extrahepatic metastasis or the treatment modality. The prevalence of comorbidities in the super-elderly group was higher than that in the younger group (P = 0.03). Survival The median follow-up duration was 18 months (range, 1 85). During the follow-up period, 17 (45.9%) patients in the super-elderly group and 97 (57.4%) patients in the younger group died. There were no significant differences in the OS or disease-specific survival (DSS) rates between the two groups. The 1-, 3- and 5-year OS rates in the super-elderly and younger groups were 80.0%, 69.7% and 38.7%, and 70.8%, 49.0% and 33.7%, respectively (P = 0.171) (Fig. 1). The 1-, 3- and 5-year DSS rates in the super-elderly and younger groups were 84.9%, 70.8% and 51.5%, and 74.0%, 55.9% and 41.3%, respectively (P = 0.176) (Fig. 2). When the patients were divided into two groups according to their age at inclusion, the super-elderly group (n = 6; 85 years) and a younger group (n = 200; <85 years), there were also no significant differences in the OS (P = 0.241) or DSS (P = 0.33) rates between the two groups. Subsequently, we performed a subclass analysis to exclude the possible effects of the tumor stage or treatment modality on DSS. The DSS rates between the two groups were compared according to the CLIP score and treatment Figure 1 The overall survival curves according to the patient age. The 1-, 3- and 5-year overall survival rates in the super-elderly and younger groups were 80.0%, 69.7% and 38.7%, and 70.8%, 49.0% and 33.7%, respectively (P =0.171). Figure 2 Disease-specific survival curves according to the patient age. The 1-, 3- and 5-year disease-specific survival rates in the super-elderly and younger groups were 84.9%, 70.8% and 51.5%, and 74.0%, 55.9% and 41.3%, respectively (P =0.176).

5 Hepatology Research 2016; 46: E5 E14 Super-elderly patients with HCC E9 modality. There were no significant differences in the DSS rates between the two groups based on a CLIP status of 0/1 (P = 0.952; Fig. 3a), 2/3 (P = 0.412; Fig. 3b) and 4 6 (P = 0.144; Fig. 3c), although the number of superelderly patients in the CLIP 2/3 (n = 5) and 4 6 groups was small (n = 3). There were no significant differences in the DSS rates between the two groups according to the use of curative treatment (P = 0.763; Fig. 4a) versus noncurative treatment (P = 0.068; Fig. 4b). There were no significant differences in the proportion of liver-related deaths (super-elderly group, 76.5%; younger group, 84.5%) and deaths due to other causes (super-elderly group, 23.5%; younger group, 15.5%) between the two groups (P = 0.878; Table 2). Prognostic factors The results of the univariate and multivariate analyses are shown in Tables 3 and 4. The multivariate analysis revealed that only the CLIP score (hazard ratio [HR], 2.972; P < ; HR, 3.694; P < ) was independently associated with the OS and DSS. Age or Figure 3 Disease-specific survival curves according to the Cancer Liver Italian Program (CLIP) score. There were no significant differences in the disease-specific survival rates between the two groups based on a CLIP status of (a) 0/1 (P =0.952), (b) 2/3 (P =0.412)and(c)4 6 (P =0.144).

6 E10 A. Kinoshita et al. Hepatology Research 2016; 46: E5 E14 Figure 4 Disease-specific survival curves according to the treatment modality. There were no significant differences in the diseasespecific survival rates between the two groups according to the use of (a) curative treatment (P = 0.763) versus (b) non-curative treatment (P =0.068). Table 2 Comparison of the causes of mortality Liver-related death (%) Other cause of death (%) Super-elderly group (n =17) Younger group (n =97) 13 (76%) 82 (85%) (24%) 15 (15%) comorbidities were not found to be associated with the OS or DSS in either the univariate or multivariate analysis. DISCUSSION BETWEEN THE AGES of 20 and 70 years old, there is a decline in hepatic volume (25%) and hepatic blood flow (30 40%). There is a decrease in the liver metabolic capacity with age, including reduced cytochrome P450 activity, a decreased liver regeneration capacity and a decrease in immunity, which lead to an increased risk of drug-induced liver damage and serious viral hepatitis in the elderly Moreover, elderly patients have more comorbidities such as cardiovascular and cerebrovascular disease, pulmonary disease, renal disease, locomotor diseases and other malignant tumors, compared with younger patients. Therefore, the management of elderly patients with HCC is more complicated and requires more attention than that of younger patients. P In the present study, we demonstrated that the proportion of women was higher in super-elderly HCC patients than that in the younger HCC patients, and that the presence of cirrhosis in super-elderly HCC patients had a tendency to be lower than that in younger HCC patients. The clinical characteristics of elderly HCC patients have been reported in several previous studies. One characteristic is that elderly HCC patients were more likely to be female, which is consistent with our results. This finding is associated with the longer life expectancy of women Second, elderly HCC patients were likely to be infected with HCV, whereas HBV infection was less common. This finding may be explained by the fact that HCV infection generally occurs later in adult life, whereas HBV infection is largely acquired by mother child transmission in the perinatal period. 22,25,26 Third, the proportion of HCC patients who were negative for both HBV and HCV infections was higher in the elderly than in the younger patients. 12,24,25 This finding is likely associated with the increasing incidence of non-alcoholic steatohepatitis-related HCC in elderly patients. 27 Fourth, elderly patients tend to develop HCC without cirrhosis or liver fibrosis, which is consistent with our results. 12,24,25 Recently, Tokushige et al. demonstrated that cryptogenic HCC patients aged 80 years and older tended to develop HCC without cirrhosis and diabetes. 28 The development of HCC without viral hepatitis or cirrhosis in elderly patients also indicates that elderly HCC patients

7 Hepatology Research 2016; 46: E5 E14 Super-elderly patients with HCC E11 Table 3 Prognostic factors for the overall survival identified by the univariate and multivariate analyses Variable Univariate analysis P Multivariate analysis Hazard ratio (95% CI), P Age 80 years Sex (male/female) HBsAg or HCVAb (positive/negative) AST 2 normal limit (IU/L) < ALT 2 normal limit (IU/L) Total serum bilirubin 2.0 (mg/dl) < Creatinine 1.5 (mg/dl) Albumin 3.5 (g/dl) < Platelet count 10 ( 10 4 /mm 3 ) Prothrombin time 70 (%) α-fetoprotein level 400 (ng/ml) < Child Pugh grade (A/B/C) < MELD score 10 < CLIP score (0/1/2/3/4/5/6) < ( ), < BCLC stage (0/A/B/C/D) < Maximum tumor diameter 50 (mm) < Tumor number (solitary/multiple) < Vascular invasion (absent/present) < Extrahepatic metastasis (absent/present) < Treatment modality (curative/non-curative) < Comorbidities (absent/present) ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer classification; CI, confidence interval; CLIP, the Cancer of the Liver Italian Program; HBsAg, hepatitis B surface antigen; HCVAb, hepatitis C antibody; MELD, Model for End-Stage Liver Disease. may have a better preserved liver functional reserve compared with younger HCC patients. The prevalence of a normal liver in the elderly HCC patients was also reported to be higher than that in the younger HCC patients. 24,25 These findings suggest that aging itself may be a potential risk factor for hepatocarcinogenesis. 25 In fact, the reduction of telomere length and hypermethylation of DNA, which are attributable to liver fibrosis and HCC, are reported to be associated with aging. 25,29 31 More recently, Katsuta et al. showed that there was age-related upregulation of the androgen and phosphatidylinositol 3-kinase pathways in the tumor tissue and downregulation of the fibrosis-related pathways in the non-cancerous liver tissue. 12 In the current study, no significant differences in either the OS or DSS were observed between the super-elderly HCC patients and younger patients. Moreover, in the multivariate analysis, high age was not associated with either the OS or DSS. Several investigators have previously reported that surgical resection is safe and feasible in HCC patients aged 80 years and older, and that there were no significant differences in the postoperative complication rates and long-term outcomes compared with those of younger patients In a recent systematic review, Oishi et al. demonstrated that the OS rates after surgical resection in elderly HCC patients at 5 years ranged %, which was not different from that observed in the younger HCC patients. 32 Radiofrequency ablation, TACE and sorafenib administration were also reported to be safe and effective in elderly patients However, unlike our study, most of these previous reports regarding the outcomes of RFA and TACE in elderly HCC patients defined elderly patients as those aged 75 years or older ,38 Considering the average current life expectancies of 80-year-old men and women in Japan (men, 8.61 years; women, years), 5 it is increasingly important to evaluate the therapeutic safety and long-term outcomes in cancer patients aged 80 years and older. In this context, our findings that both the OS and DSS in super-elderly HCC patients over 80 years old not indicated for surgical resection were comparable with those in younger patients are meaningful for this aging society. Consistent with previous reports, our current study demonstrated that super-elderly HCC patients had more comorbidities, which could affect the patients outcomes, than younger patients. Despite having more comorbidities, most of the elderly HCC patients over

8 E12 A. Kinoshita et al. Hepatology Research 2016; 46: E5 E14 Table 4 Prognostic factors for the disease-specific survival identified by the univariate and multivariate analyses Variable Univariate analysis P Multivariate analysis Hazard ratio (95% CI), P Age 80 years 0.18 Sex (male/female) HBsAg or HCVAb (positive/negative) AST 2 normal limit (IU/L) < ALT 2 normal limit (IU/L) 0.13 Total serum bilirubin 2.0 (mg/dl) < Creatinine 1.5 (mg/dl) Albumin 3.5 (g/dl) < Platelet count 10 ( 10 4 /mm 3 ) Prothrombin time 70 (%) α-fetoprotein level 400 (ng/ml) < Child Pugh grade (A/B/C) < MELD score 10 < CLIP score (0/1/2/3/4/5/6) < ( ), < BCLC stage (0/A/B/C/D) < Maximum tumor diameter 50 (mm) < Tumor number (solitary/multiple) < Vascular invasion (absent/present) < Extrahepatic metastasis (absent/present) < Treatment modality (curative/non-curative) < Comorbidities (absent/present) ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer classification; CI, confidence interval; CLIP, the Cancer of the Liver Italian Program; HBsAg, hepatitis B surface antigen; HCVAb, hepatitis C antibody; MELD, Model for End-Stage Liver Disease. 80 years old died from HCC-related causes. Moreover, there were no significant differences in the proportion of liver-related deaths and deaths due to other causes between the two groups. Therefore, aggressive and curative treatment may improve the survival outcomes and be justified even in super-elderly HCC patients over 80 years old. 10,40 However, in the current study, both the OS and DSS curves in the super-elderly group showed a precipitous drop and crossed those noted in the younger group after 60 months of the initial treatment. This is partly because a decline in the performance status and/or increase in comorbidities associated with age might have affected the patients survival after 60 months of treatment. Therefore, in each therapeutic session, it is necessary to reconsider the therapeutic approach, particularly in super-elderly HCC patients, according to secular changes in the performance status and comorbidities. In daily clinical practice, physicians struggle to determine at what age to treat patients with HCC. In the current study, the overall median survival and DSS periods in the super-elderly group were 56 and 66 months, respectively. Considering the average current life expectancies of 80-, 85- and 90-year-old men and women in Japan (men, 8.61, 6.12 and 4.26 years; women, 11.52, 8.19 and 5.53 years, respectively), it is possible to extend the life prognosis of super-elderly patients until 85 years of age in the calculation. However, these issues must be addressed in a large-scale prospective validation study. When discussing the treatment and survival outcomes of elderly patients with HCC, clinicians should be aware of the following limitations. First, there may have been an unintentional selection bias, because we tend to select elderly patients with a good performance status and preserved liver functional reserve, which may favor comparable outcomes to those of younger patients. On the contrary, another potential selection bias, wherein we tend to select non-curative palliative treatment based only on advanced age itself may favor poorer outcomes compared with younger patients. In fact, in the current study, there was a difference in the proportion of patients treated with surgical resection between the super-elderly (0/38, 0%) and younger (19/203, 9.4%) groups (P = 0.102) (although 19 patients who underwent surgical resection were excluded in the current analysis). Several investigators showed that elderly patients with

9 Hepatology Research 2016; 46: E5 E14 Super-elderly patients with HCC E13 HCC had a worse survival outcome compared with younger patients due to the tendency for them to receive less aggressive and non-curative treatment. 41,42 The current study is associated with some other limitations. First, it was a retrospective and single-center study. Therefore, the possibility of unintentional selection bias in the selection of patients could not be fully excluded, as noted above. Moreover, because our hospital is a university hospital, there might have been an intentional treatment and possible hospital bias. Second, the therapeutic effects of the second and third lines of treatment for HCC were not evaluated as prognostic factors. Because many patients received multiple treatments due to HCC recurrence during their follow-up period, it has been difficult to evaluate all of the therapeutic effects as prognostic factors in this patient population. Therefore, our findings need to be confirmed in a prospective study. In conclusion, we herein demonstrated that there were no significant differences in the OS and DSS rates among the super-elderly HCC patients and younger HCC patients not indicated for surgical resection, and that a high age ( 80 years) was not found to be associated with the OS or DSS. An advanced age itself does not restrict the therapeutic approach, even in super-elderly HCC patients not indicated for surgical resection. ACKNOWLEDGMENTS WE ARE VERY appreciative of the efforts of Junko Hijikata, Haruna Ono and Kaori Murata in the data acquisition. REFERENCES 1 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet : Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut : Liver EAFTSOT, Cancer EOFRATO. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. JHepatol : El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology : Ministry of Health, Labor and Welfare 2013.In: Japanese simple life table saikin/hw/life/life13/index.html. Accessed 26 Nov Wu CC, Chen JT, Ho WL, Yeh DC, Tang JS, Liu TJ, P eng FK. Liver resection for hepatocellular carcinoma in octogenarians. Surgery : Hazama H, Omagari K, Matsuo I, et al.. Clinicalfeatures and treatment of hepatocellular carcinoma in eight patients older than eighty years of age. Hepatogastroenterology : Shirabe K, Kajiyama K, Harimoto N, et al. Early outcome following hepatic resection in patients older than 80 years of age. World J Surg : Nanashima A, Abo T, Nonaka T, et al. Prognosis of patients with hepatocellular carcinoma after hepatic resection: are elderly patients suitable for surgery? JSurgOncol : Yamada S, Shimada M, Miyake H, et al. Outcome of hepatectomy in super-elderly patients with hepatocellular carcinoma. Hepatol Res : Tsujita E, Utsunomiya T, Yamashita Y, et al. Outcome of hepatectomy in hepatocellular carcinoma patients aged 80 years and older. Hepatogastroenterology : Katsuta E, Tanaka S, Mogushi K, et al. Age-related clinicopathologic and molecular features of patients receiving curative hepatectomy for hepatocellular carcinoma. Am J Surg : Nozawa A, Kubo S, Takemura S et al. Hepatic resection for hepatocellular carcinoma in super-elderly patients aged 80 years and older in the first decade of the 21st century. Surg Today [Epub ahead of print.] 14 The Cancer of the Liver Italian Program (CLIP) investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology : Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis : Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg : Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology : Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med : Frith J, Jones D, Newton JL. Chronic liver disease in an ageing population. Age Ageing : Gan L,Chitturi S,FarrellGC.Mechanisms and implications of age-related changes in the liver: nonalcoholic Fatty liver disease in the elderly. Curr Gerontol Geriatr Res : Carrion AF, Martin P. Viral hepatitis in the elderly. Am J Gastroenterol : Mirici-Cappa F, Gramenzi A, Santi V, et al. Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience. Gut : Kozyreva ON, Chi D, Clark JW, Wang H, Theall KP, Ryan DP, Zhu AX. A multicenter retrospective study on clinical characteristics, treatment patterns, and outcome in elderly patients with hepatocellular carcinoma. Oncologist :

10 E14 A. Kinoshita et al. Hepatology Research 2016; 46: E5 E14 24 Honda T, Miyaaki H, Ichikawa T, et al. Clinical characteristics of hepatocellular carcinoma in elderly patients. Oncol Lett : Nishikawa H, Kimura T, Kita R, Osaki Y. Treatment for hepatocellular carcinoma in elderly patients: a literature review. JCancer2013 4: El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology : Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology : Tokushige K, Hashimoto E, Horie Y, Taniai M, Higuchi S. Hepatocellular carcinoma based on cryptogenic liver disease: the most common non-viral hepatocellular carcinoma in patients aged over 80 years. Hepatol Res [Epub ahead of print.] 29 Ahuja N, Li Q, Mohan AL, Baylin SB, Issa JP. Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res : Isokawa O, Suda T, Aoyagi Y, et al. Reduction of telomeric repeats as a possible predictor for development of hepatocellular carcinoma: convenient evaluation by slotblot analysis. Hepatology : Shen L, Ahuja N, Shen Y, Habib NA, Toyota M, Rashid A, Issa JP. DNA methylation and environmental exposures in human hepatocellular carcinoma. J Natl Cancer Inst : Oishi K, Itamoto T, Kohashi T, et al. Safety of hepatectomy for elderly patients with hepatocellular carcinoma. World J Gastroenterol : Hiraoka A, Michitaka K, Horiike N, et al. Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients. J Gastroenterol Hepatol : Yamazaki H, Tsuji K, Nagai K, et al. Efficacy and long-term outcomes of radiofrequency ablation in the elderly with hepatocellular carcinoma. Hepatol Res : Cohen MJ, Bloom AI, Barak O, et al. Trans-arterial chemoembolization is safe and effective for very elderly patients with hepatocellular carcinoma. World J Gastroenterol : Nishikawa H, Kita R, Kimura T, et al. Transcatheter arterial chemoembolization for intermediate-stage hepatocellular carcinoma: clinical outcome and safety in elderly patients. J Cancer : Jo M, Yasui K, Kirishima T, et al. Efficacy and safety of sorafenib in very elderly patients aged 80 years and older with advanced hepatocellular carcinoma. Hepatol Res : Takahashi H, Mizuta T, Kawazoe S, et al. Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients. Hepatol Res : Ishikawa T. Radiofrequency ablation is justified for elderly patients with hepatocellular carcinoma. Hepatol Res : Tsukioka G, Kakizaki S, Sohara N, et al. Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival. World J Gastroenterol : Pignata S, Gallo C, Daniele B, et al. Characteristics at presentation and outcome of hepatocellular carcinoma (HCC) in the elderly. a study of the Cancer of the Liver Italian Program (CLIP). Crit Rev Oncol Hematol : Hori M, Tanaka M, Ando E, et al. Long-term outcome of elderly patients (75 years or older) with hepatocellular carcinoma. Hepatol Res :